Review: The Patent War Behind the First $10 Billion Variety in Pharmaceutical History

"Patents are the oil of profit for the fire of genius, " Lincoln's famous saying, confirming the growth of one billion or even ten billion dollars of molecules after another in pharmacy, and some economists say that "without patent protection, 60% of new drugs would not have been invented".
shows how important it is for the development of new drugs to be protected through the disclosure of knowledge.
The first $10 billion variety in the history of pharmaceuticals, Lipto, has enjoyed the dividends of the patent system, but what the U.S. and China have not done enough in terms of public exchange for protection seems unsatisfactory, which is one of the reasons for the ongoing patent disputes in its later years.
01 Lipto (Atovastatin) Introduction First developed by Warner-Lambert as HMG-CoA reductase inhibitor, listed in the United States in 1997 for the treatment of hypercholesterolemia and coronary heart disease; There have been a number of patents for Atovastatin, which was acquired by Warner-Lambert for $82.4 billion; in 2004, Atovastatin became the first drug in history to have sales of more than $10 billion (peaking at nearly $13 billion); and patent-period sales totaled more than $130 billion.
Figure 2: Lipto Global Sales 02 Core Patent Distribution Compound Patent, Patent No. US4681893, application dated May 30, 1986, authorized on July 21, 1987, since the drug market, the patent has been extended to March 24, 2010.
crystal patent, patent number US5969156, the earliest filing date is July 17, 1995 (i.e., priority date), is a "temporary patent application", July 8, 1996 filed a formal patent application, the patent period from the official patent application date of 20 to July 8, 2016;
10 July 2002, atovastatin-related crystal patents were granted in China (application number: 96195564.3, application date: 8 July 1996).
after the trial, the first instance, the second instance, up to the Supreme Court, was eventually declared null and void.
PS: The European generic patent EP848705B in this case was challenged by Teva and LEK and was eventually revoked on February 25, 2009 due to insufficient disclosure.
same-family patent JP3296564B2, which is the patent in this case, was also declared invalid on February 15, 2012 (No. 2010-800235).
U.S. mainland, its U.S. generic patent, US5969156A, was in dispute from its 1999 license until February 6, 2012, when it was sued.
03 The invalidity process of domestic cases - In early 2007, the patente (Pfizer) filed a civil suit with a Chinese court in Beijing, allring accusing Beijing Jialin Pharmaceutical Co., Ltd. ("Carlin Company") of infringing the patent rights of the generic drug "Ale" (formerly Pfizer's "Lipto"), after which the plaintiff had to withdraw the suit because of insufficient evidence.
From June 2007 to May 2008, Jialin Company and Zhang Chu (public interest litigation) filed three applications for invalidity with the Patent Review Board of the State Intellectual Property Office for the patent rights of the attovastatin calcium type I crystal.
the review committee formed an expanded five-member d's panel to hear the case, two oral hearings of the case, and in mid-2009 made the 13582 examination decision, found that the patent description did not make a clear and complete description of the patent protection of hydrate crystal inventions, and thus declared it all invalid.
the patente, who did not accept The 13582 review decision, filed an administrative lawsuit with a Chinese court in Beijing, in which Jialin participated as a third party.
court of first instance, after a hearing, issued administrative judgment No. 2710 (2009) on 14 May 2010, upholding review decision No. 13582.
. - The patente appealed to the Beijing High Court against the administrative judgment No. 2710 of the first word of the Chinese Bank of Knowledge, and Jialin Company participated in the appeal process as a third party.
At the hearing of the court of second instance, the patentor added an experimental report intended to show that, in accordance with the general disclosure in the manual and the specific disclosure of the implementing practice, it was possible to prepare a type I crystalline atovastatin hydrant with three moles of water, as defined in claim 3.
after the court of second instance, on May 15, 2012, it issued an administrative judgment No. 1489, which annulled the first instance judgment, annulled the examination decision No. 13582, and the decision review committee re-issued a request for examination of the invalid declaration of invention patent No. ZL96195564.3.
In order to test the correctness of the experimental methods and conclusions of the experimental report, Jialin also commissioned the Beijing Guowei Intellectual Property Judicial Identification Center to issue a judicial appraisal opinion and submit it to the Supreme Court.
the Supreme Court, after a hearing, at the end of 2013 issued (2013) no. 16 administrative ruling, ruling that the case entered the formal adjudication process.
Supreme Court issued Administrative Judgment No. 8 (2014) on 16 April 2015, and the case was ultimately null and void.
figure 4: Supreme Law Administrative Judgment 04 The focus of the case is whether the patent protection of the type I crystalline attovastatin hydrate containing 1 to 8 molar water is fully disclosed in the manual, the main points of contention are as follows: 1) Hydrate containing the same compound of different molar water, its XPRD and 13CNMR are the same? 2) According to the contents disclosed in the instructions can confirm that the type I crystalline atovastatin hydration contains 1 to 8 moles of water? 3) According to the contents disclosed in the manual, can skilled personnel in the art prepare the type I crystalline atovastatin hydration containing 1 to 8 moles of water? 05 The requester's opinion It is well known in this field that the crystallization water will stand in the cell and get different cell structures, which will inevitably result in different XPRD maps and solid state 13CNMR.
the same time, the technical programme for claim 1 was not fully disclosed in the statement, and for similar reasons, the technical programme for claim 2 was not fully disclosed in the manual.
claims the protection of type I crystalline attovastatin hydrates containing 1 to 8 moles of water, including 8 types of type I crystallization, but the instructions do not verify that these 8 types of I crystalline hydrates have the same XPRD and 13CNMR, and whether based on the general disclosure of the instructions or the disclosure based on the implementation of the case, it is difficult for technical personnel in the art to prepare the type I crystalline attovastatin water with 1 to 8 molar water. The
statement only asserts that type I crystalline atovastatin hydration can overcome non-stereotyped technical defects, but they are not proved by qualitative or quantitative experimental data, and that part of the defects also exist in the present invention.
, type I crystallization has the potential to reduce bio-utilization.
06 Right-to-rights Opinion The requestor's assertion that crystals and crystalline hydrates of different crystalline water must have different XPRD cannot be established, and there is evidence that solvent and non-solventized crystals with different water content can have almost identical XPRD.
those skilled in the field based on the contents of the instruction manual can know that the patented X-ray diffraction map corresponds to type I crystals, its water content can vary within a certain range, claim 1 requirements to protect the I-type crystals containing 1 to 8 moles of water.
requestor did not prove that the water content of different crystals its 13CNMR is necessarily different, those skilled in the field according to the contents of the manual can implement the technical scheme of claim 2, therefore, claim 2 is fully open.
manual discloses the structure and analytical data of the type I crystalline Atovastatin hydrant containing 1 to 8 moles of water in this patent, and discloses its preparation method, the preparation implementation case and its beneficial effect.
evidence shows that the water in the hydration crystal can exist in the form of crystalline water, or it may not exist in the form of crystalline water, and there is expert testimony that the patent belongs to the latter.
07 Invalidity Decision Points Although there is evidence that solventization and non-solventization crystallization can have almost identical XPRD for individual compounds, water in hydrates of most substances in this field is positioned in the cells and produces different XPRDs.
In the case of a particular hydrant crystal, there is no uniform teaching in this field as to whether the water in the hydration will occupy, whether the presence of water or the amount of water content will affect its XPRD.
, this patent does not provide the corresponding evidence.
The crystalline product protected by claim 1 to 3 is defined by its composition (atovastatin, water content) and microstructure (XPRD or 13CNMR), and the water content is an essential part of the product composition, however, the manual only states that its water content is 1 to 8 moles, preferably 3 moles, but does not provide any qualitative or quantitative data to prove that the resulting type I crystalline attovata The hydration does contain 1 to 8 moles (preferably 3 moles) of water, and even the most specific example 1 does not measure the water content in its product;
, those skilled in the technology can't identify the products protected in the claim based on the contents disclosed in the instructions.
In this case, the method of preparation of type I crystallization as documented in the preparation of the implementation case uses the crystalline type I, which is not only one of the raw materials of the preparation method but also the target product, such preparation method is undoubtedly a dead cycle for the technical personnel in the technical field, can not obtain the type I crystallization as the target product, the preparation application itself is not disclosed how to produce type I crystallization.
In this general preparation method, some specific process conditions, such as including one of the most important conditions in crystallization operation - cooling speed, are not mentioned, need to explore the choice, whether creative labor or excessive labor is required in the meantime is not known, the technical field of technical personnel can prepare to obtain the target product is a question.
In fact, type I crystallization is really difficult to prepare, according to the evidence submitted by the patente, in the case of the existing type I crystallization as a crystal species, the method of repeating example 1, example 1 records heating for at least 10 minutes, while the patente repeated when the actual heating for more than 10 hours.
according to the existing crystal preparation implementation example is still so difficult to prepare the crystallization, no crystal species lack of specific process conditions of the pan-pan preparation method.
08 The Supreme Court found that there is a logical relationship between the reproduction of technical programs and whether they solve technical problems and the evaluation of technical effects, and should first confirm whether those skilled in the field can realize the technical program according to the contents disclosed in the instructions, and then confirm whether they have solved the technical problems and produced technical effects, and whether they can solve the corresponding technical problems compared with the existing technology and achieve beneficial technical effects.
In this case, the court of second instance did not actually consider the realization of the technical scheme qualified by this patent claim, but first considered the technical problems to be solved by the invention, and then considered the chemical and physical performance parameters related to the technical problems to be solved, the trial was not properly considered and corrected by the Court.
Lombo argues that the nature of the water in the type I crystalline Atovastatin hydrant protected by this patent is channel water, which changes within a specific 1-8 mole range and does not affect XPRD.
In this regard, the Court considers that there is no uniform teaching in the field as to whether water in a substance's hydrated matter will occupy, whether the presence of water or the amount of water content affects its XPRD, and that Warnier Lamber should provide evidence to support this claim.
This patent statement only claims that the waterless and hydrated forms in this patent are equivalent, but the water in the I. crystalline Atovastatin hydration belongs to the "water does not occupy, does not affect the crystal XPRD" substance, or belongs to the "water will occupy, will affect the crystal XPRD" substance, Warnier Lamber company has no evidence.
A step back, even if, as Warnier Lamber claims, the channel water does not occupy a position in the hydrated and does not affect the crystal XPRD, Warnier Lamber has no evidence that the water in the I. crystalline Atovastatin hydration as defined in this patent claim belongs to the channel water.
Wonier Lamber recognizes how much water is contained in type I crystalline attovastatin not determined in this patent description, and also recognizes that the map disclosed in this patent manual does not in itself determine the water content of the corresponding compound, and that those skilled in the art are unable to confirm that the I. crystalline attovastatin hydrate protected by this patent request does contain 1 to 8 molars of water, preferably 3 molars of water.
Secondly, according to the definition of crystalline water and hydration in evidence 4 and 6 submitted by Jialin Company above, the nature of the water contained in the I. crystalline attovastatin hydration protected by this patent shall be crystalline water, not adsorption water.
But crystalline water also includes channel water and occupied water entering the lattic grid, these different forms of water and crystal binding degree is different, directly determines the stability of these water molecules in the crystal.
According to the relevant records of this patent specification as identified by this Court, meeting strict drug requirements and specifications and having better storage stability are also technical problems that must be solved by the present invention, and the water content and water presence in hydration directly affect the resolution of the above-mentioned technical problems.
There is currently no evidence of the specific presence of water in the I. type crystalline attovastatin hydration protected by this patent request, and those skilled in the art are unable to confirm the I. crystalline attovata protected by this patent request according to the contents of this patent statement